Extended release solid compositions are preferred dosage forms over immediate release solid compositions, especially for active ingredients showing fluctuations in the plasma concentration and for active ingredients having short half-lives. Extended release solid compositions can be in the form of tablets or capsules, wherein the release of the active ingredient is controlled by using a reservoir or a matrix system. However, extended release solid oral compositions suffer from certain drawbacks such as difficulty in swallowing, particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor patient compliance. Further, high doses of active ingredient lead to large-sized compositions which aggravates this problem. Also, there remains a tendency to divide extended release solid compositions such as tablets into small pieces in order to facilitate administration, which may ultimately lead to inaccurate dosing and/or dose dumping. In view of all this, extended release liquid compositions provide the best alternative over extended release solid compositions. Extended release liquid compositions are easy to administer, thereby leading to enhanced patient compliance. Additionally, extended release liquid compositions provide a unique advantage of having a flexible dosing regimen.
Although extended release liquid compositions are advantageous, there remain some complexities involved in formulating such compositions. The important prerequisite of these compositions is to provide the desired extended release of the active ingredient throughout its shelf life, as irregular release may lead to sub-therapeutic or toxic effects. The key hurdle remains to overcome the leaching of the active ingredient from the coated cores into a suspension base during storage. The objective for a scientist remains to develop a formulation such that the release of the active ingredient into the suspension base during storage is avoided, and only when the suspension enters the gastrointestinal tract the release is allowed.
The prior art discloses various approaches to overcome the leaching problem for the preparation of extended release liquid compositions.
PCT Publication No. WO 2012/063257 and U.S. Publication No. 2008/0118570 disclose extended release suspensions employing ion-exchange resins. Although ion-exchange resin systems provide the desired extended release of the active ingredient without significant leaching during storage, these systems require chemical binding of the active ingredient to the resin, which is complicated and not suitable for many active ingredients.
PCT Publication No. WO 2011/107855 discloses a ready to use sustained release oral suspension comprising inert pellets surrounded by a seal coating, an active ingredient layer surrounding the seal coated inert pellets, and a coating layer comprising a rate-controlling polymer surrounding the active ingredient layer. Said sustained release pellets are further coated with a protective coating layer which prevents the leaching of the active ingredient.
PCT Publication No. WO 2008/122993 discloses a suspension of an active ingredient containing microparticles with at least one coat of a pH-independent polymer. Further, there is an additional coat of pH-dependent polymer which provides stability to the formulation by avoiding leaching of active ingredient in the liquid phase after reconstitution during storage.
In the formulations disclosed in these prior art, the leaching of the active ingredients from the coated units into the media during storage is primarily prevented by the use of a multiple coating systems. However, the process of applying multiple coating systems remains time-consuming, complicated, and difficult to be functionally reproducible.
U.S. Pat. No. 7,906,145 discloses a sustained release suspension comprising microcapsules suspended in an aqueous liquid phase saturated with an active ingredient, wherein each microcapsule comprises a core of the active ingredient and a coating layer applied to the core which controls the modified release of the active ingredient in gastrointestinal fluids. Said coating layer comprises a film-forming polymer, a nitrogen-containing polymer, a plasticizer, and a surfactant/lubricant. The coating layer is designed in a way such that the release profile is not perturbed in the liquid phase and the active ingredient contained in the microcapsules is prevented from escaping into the liquid phase throughout the storage of the suspension. However, this system also requires mandatory use of an aqueous phase saturated with the active ingredient which may not be suitable for active ingredients having low aqueous solubility and/or low dose. Further, this system is limited to class of active ingredients which require an immediate dose or an initial spike in the release profile and therefore is not suitable for active ingredients which do not require any immediate dose of the active ingredient. Also, the aqueous phase saturated with the active ingredient remains physically unstable as a small variation in temperature, pH, and/or ionic concentration may lead to salting out or precipitation of the active ingredient.
In view of all these, there remains a need in the art to formulate extended release suspension compositions of the active ingredients which are based on a simplified and robust technology and which provide significant advancement over the existing prior art. The extended release suspension compositions of the present invention are suitable for variety of active ingredients including active ingredients having low aqueous solubility or active ingredients which do not require any immediate dose of the active ingredient. The extended release suspension compositions of the present invention remain physically stable to any variation in temperature, pH, and/or ionic concentration. Furthermore, the extended release suspension compositions of the present invention provide the desired extended release throughout the shelf life of the compositions.
The present invention provides extended release suspension compositions based on a simplified technology, prepared by a process which is relatively simple, easy to commercially manufacture, and functionally reproducible. The present invention uses a unique suspension base which prevents the leaching of the active ingredient from the coated cores during storage. The suspension base thus ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage throughout the shelf life of the compositions. This consistent in-vitro release then ensures a steady plasma concentration with no fluctuations throughout the shelf life of the compositions. Additionally, the extended release suspension compositions of the present invention are able to incorporate two or more active ingredients with different release profiles or two or more incompatible active ingredients in a single composition.